We propose to confirm and extend our observations that susceptibility to phenytoin-induced cleft palate in inbred strains of mice is regulated by a gene in or near the H-2 histocompatibility locus. If so, we hypothesize that the molecular mechanism by which the hydantoins induce human cleft palate is similar to our recent observations on corticoid induced cleft palate, namely, binding of corticoids to cytosol receptors, uptake by nuclei, and activation or depression of transcription or translation. Binding of 3H-dilantin will be studied in palatal mesenchymal cells of sensitive strains of mice by conventional techniques and by our micromethods of isoelectrofocusing. Dilantin and other cleft palate teratogen receptors will also be sought in palatal and skin fibroblast cultures of infants with and without cleft palates with the hope that receptor levels can be shown to be a controlling factor in human cleft palate. If dilantin is given at an early stage in mice, it also produces cleft lip and cleft palate. We propose to include the study of dilantin induced cleft lip and palate in mice as a model of the fetal dilantin syndrome. Dilantin can form a reactive epoxide intermediate which may be related to its teratogenicity. The known differences in mixed function oxidase enzyme system in cleft palate susceptible and resistant strains of mice may account for the formation of this intermediate which may covalently bind to target tissues at a critical period. We would also like to delineate the enzymatic reactions involved in phenytoin metabolism and identify the contribution of the parent compound or its metabolite(s) to the teratogenic effect. In short, we hope to delineate the molecular chain of events involved in the action of a teratogenic drug in both animals and humans with cleft (lip) palate as a model of drug-induced craniofacial anomalies.